CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority of U.S. Provisional Application Ser. No.

62/676,305 entitled "METHODS AND SYSTEMS FOR STABLE ADHESIVES", filed May 25, 2018, the disclosure of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION

[0003] Aspects of the disclosed subject matter include methods and systems for formulating, packaging, sterilizing, and delivering stable adhesives and systems used for medical purposes, such as wound closure in humans and other living beings.

[0004] BACKGROUND

[0005] The functionality of medical adhesives and devices used to deliver medical adhesives to a patient’s skin are dependent on the ability of a liquid adhesive’s formulation to be delivered to the patient’s skin in liquid form. The liquid must then polymerize to form a thin polymer film with both strong adhesive and tensile properties. The attributes of such adhesive formulations that enable maximum performance include controlled viscosity and reactivity. Viscosity is the thickness of the liquid is typically measured in centipoise.

Reactivity is the ability of the adhesive to polymerize effectively without excess heat which could damages the skin, this property is usually specified in seconds.

[0006] Viscosity can be adversely affected by both temperature or impurities introduced into the formulation. Both of these factors can partially initiate polymerization in the liquid, creating polymerized chains within the adhesive. These chains increase liquid’s viscosity and bind portions of the monomer. The bound portions are no longer free to react when applied to the skin, thus slowing the reaction time, causing slow polymerization and reducing performance. [0007] Of particular concern is the presence of moisture as an impurity in the adhesive formulation. Moisture can lead to premature polymerization as described above, and also over the time, such as during storage, and can lead to increased acidity of the formulation, further slowing reaction time. Acids can be used as stabilization agents for cyanoacrylate adhesives, thus limiting their ability to polymerize.

[0008] Therefore, measures must be taken to reduce the exposure of the formulation to heat during processing, and to ensure that the adhesive remains free of impurities, particularly moisture. It is therefore desirable to improve methods and systems for producing stable adhesives to maximize shelf life and increase stability over time due to heat and or moisture.

SUMMARY

[0009] In one non limiting aspect of the present invention a method for

manufacturing a stable adhesive composition includes the steps of: combining a first plurality of adhesive components in a vessel thereby forming a mixture; heating the mixture to about 109 degrees C; stirring the mixture for at least one hour; adding a second plurality of adhesive components to the mixture while stirring the mixture; filtering the mixture through a filter cloth, thereby removing any insolubilized material; transferring the mixture to a storage vessel; maintaining the storage vessel at a temperature of between about 4 degrees C and about 8 degrees C; and stabilizing the mixture using a sulfur dioxide gas stream.

[0010] In some embodiments, the first plurality of adhesive components includes about

85% 2-octyl cyanoacrylate and about 3.7% poly (methyl methacrylate).

[0011] In other embodiments, the second plurality of adhesive components includes about 4.8% tributyl O-acetylcitrate, about 5% acetone, and about 1% butyl hydroxyanisole.

[0012] In certain embodiments, the sulfur dioxide gas stream imparts about 0.015 weight

% sulfur dioxide to the mixture. [0013] In a particular embodiment, the filter cloth has a porosity of about 10 microns.

[0014] In some embodiments, the method further includes the steps of: warming the cooled mixture to room temperature; pumping the mixture into a cyclic olefin copolymer vial at a flow rate of about 0.15 mL/second; and sealing the vial with a coated foil lid.

[0015] In certain embodiments, the coated foil lid includes a cyclic olefin copolymer coating.

[0016] In other embodiments, the coated foil lid includes a cyclic olefin copolymer and an adhesive coating.

[0017] In some embodiments, the method further includes the step of sterilizing the sealed vial using a dose of electron beam radiation.

[0018] In certain embodiments, the dose of electron beam radiation is between about

8kGy and about 10 kGy.

[0019] In yet other embodiments, the viscosity of the stable adhesive composition increases by less than about 10% after about eight (8) days of accelerated aging.

[0020] In certain embodiments, the viscosity of the stable adhesive composition increases by less than about 50% after about forty-eight (48) days of accelerated aging.

[0021] In another aspect, a method for packaging a stable adhesive composition includes the steps of: pumping a stabilized adhesive mixture into a cyclic olefin copolymer (COC) vial at a flow rate of about 0.15 mL/second; sealing the COC vial with a coated foil lid; and sterilizing the sealed COC vial with a dose of electron beam radiation.

[0022] In a particular aspect of the present invention, a method for packaging an adhesive applicator system includes the steps of: coating a porous plug with a polymerization initiator; sealing the porous plug, an applicator, and a vial containing a stabilized adhesive composition in a foil pouch; and sterilizing the foil pouch using an ethylene oxide gas. [0023] In certain embodiments, the porous plug is comprised of polyethylene.

[0024] In some embodiments, the polymerization initiator is benzalkonium chloride.

[0025] In some other embodiments, the porous plug is saturated with a solvent solution containing benzalkonium chloride and the solvent is evaporated leaving a residue of about 7 mg of benzalkonium chloride on the porous plug.

[0026] In some embodiments, the step of sterilizing the foil pouch is performed under a partial vacuum condition.

[0027] In a particular embodiment, the partial vacuum condition is about 0.5

atmosphere.

[0028] In some embodiments, the ethylene oxide gas is maintained at a pressure of between about 28 and about 30 inHg for between about 5.5 and about 6.5 hours.

DESCRIPTION

[0029] Formulation Processes

[0030] The first step in producing novel stable adhesives is the formulation process.

The environment of the adhesive manufacturing area must be strictly controlled using an HVAC system. The operations include transfer of adhesive components in a fume hood to avoid contaminating the environment. The equipment used in the manufacturing process is purged with dry nitrogen to remove ambient atmosphere / humidity. Optimum conditions are controlled temperature in the range of 70 to 77 degrees F and relative humidity in the range of 40% to 60%. This step includes containment vessels, heating ovens, mixing kettles, and shipping vessels.

[0031] Gowning requirements for operations personnel include lab coats, hair nets, gloves, and safety glasses, to protect the personnel and the formulation.

[0032] All processing vessels are acid washed, rinsed, and dried prior to use. This step includes vessels for the bulk adhesive formulation and vessels used to transfer components. Shipping vessels are rinsed with an isopropyl alcohol / acetone solution and dried prior to use. The main components of the formulation as shown in Table 1 are added directly to the mixing kettle by weight. Components that are added in smaller amounts are weighed in separate transfer containers and subsequently added.

[0033] The thickening agent, poly (methyl methacrylate) (PMMA) is added to the adhesive monomer with stirring in the first step of the formulation process. The mixture is heated to help solubilize the PMMA in the adhesive. One particular embodiment the PMMA includes DEGACRYL ^® M449. In order to dissolve this material in 2-octyl cyanoacrylate monomer, the mixture must be heated above the softening temperature, which is about l09°C / 228°F. Once this temperature is achieved, the mixture is stirred for at least an hour to ensure uniform dissolution.

[0034] The remaining components are added with stirring and no heat. The final formulation is filtered through a filter cloth to remove any insolubilized PMMA. The filter cloth is pre-packaged in a plastic tray and is removed immediately prior to use to reduce potential contamination. The filter cloth can be made of a material that is inert with regard to

cyanoacrylate, typically polypropylene, and is rated at a porosity of about 10 microns for fine particle filtration. If the pore size is too small, the adhesive will not pass through it and if the pore size is too large, it will not screen the material properly. The process step at which filtration takes place is the final transfer of the bulk formulation into the shipping / storage vessel. The liquid formulation is poured through the filter into the final storage vessel.

[0035] After filling, the shipping container is purged with dry nitrogen to create a nitrogen head space. The shipping vessel is capped with a screw top and sealed with tape to prevent contamination. The formulation is stored under refrigerated conditions (4 - 8 °C) to limit exposure to thermal stress. The formulation is shipped with ice packs in insulated shipping boxes to limit exposure to thermal stress. Maximum temperature during shipping must be limited to no more than 50 degrees F.

[0036] Stabilization Process

In order to stabilize the formulation, sulfur dioxide is added gravimetrically by bubbling gas through the liquid formulation. The apparatus for S0 ₂ addition consists of a tank of S0 ₂ gas fitted with a pressure regulator connected to a section of flexible polyethylene tubing with a gas dispersion filter attached to the distal end. The container of liquid adhesive to be stabilized is placed on an analytical balance, and the tubing is introduced into the container and submerged in the adhesive. The pressure regulator is then opened and sulfur dioxide gas is passed into the liquid until the target addition weight is achieved. S0 ₂ is added is targeted at l50mg per lOOOg of adhesive, for a final composition of 150 ppm.

[0037] Filling Process.

[0038] The bulk adhesive must be transferred to smaller usable containers for applications. This process has a critical effect on stability.

[0039] The bulk adhesive must be allowed to warm to room temperature prior to filling however, in order for the viscosity to remain constant during the filling operation. The tubing used to transfer the adhesive from the bulk container to the filling station is specially selected for compatibility with cyanoacrylate. The tubing is flushed with adhesive prior to the start of filling to remove any particulate contamination that may be present. The tubing is replaced after each filling operation to avoid contamination due to polymerized adhesive forming within the tubing after the previous filling operation. The pumps used to transfer the adhesive from the bulk container to the filling station are calibrated to operate at low pressure. For example, it has been discovered that a peristaltic pump can be used to deliver the adhesive at a flow rate of about 0.175 mL/second to avoid shear stress on the adhesive. The adhesive is delivered into vials during the filling operation at a rate that minimizes splashing. Splashing of the adhesive onto the seal surface of the vial can result in a compromised seal and is therefore to be avoided. The optimum fill rate is between about 0.1 and about 0.2 ml/sec, preferably between about

0. l4ml/sec and about 0.l5ml/sec.

[0040] The vials are comprised of cyclic olefin copolymer (COC) resin. One such material is TOPAZ ^® 6013 COC. This resin has been specified to provide compatibility with the cyanoacrylate adhesive. The COC resin has been specified to provide an effective barrier to moisture. The dimensions of the vial including wall thickness have been optimized to provide the best possible moisture barrier properties. [0041] The vial and foil lidding system has been specified to produce optimal stability of the adhesive. The foil lidding includes a layer of foil, a layer of adhesive and a layer of COC resin in order to create an effective seal and create a hermetic seal. The COC resin (6013) provides optimal sealing and flexibility characteristics. The thickness of the foil component of the lidding is specified to have minimal defects in order to provide an effective barrier to moisture. The layer of the foil lidding that binds the foil and COC layers has been verified for compatibility with cyanoacrylate to ensure that the foil is not compromised by attack from the sealed adhesive. In a particular configuration the foil/adhesive/COC lidding system is configured to have thicknesses of between about l5-35pm/28-48pm/4l-6lpm, respectively. In a preferred embodiment, the foil/adhesive/COC lidding system is configured to have thicknesses of 25pm/38pm/5 1 p , respectively. The foil lidding system has a moisture vapor transmission rate (MVTR) and an oxygen transmission rate (OTR) of less than about 0032g/m ² /24 hours.

[0042] Compatibility of the foil with the adhesive has been demonstrated in a stability study at accelerated storage conditions of 50°C. This study determined that an estimated shelf life of 12 months was achieved for the commercial formulation packaged in COC resin vials sealed with the custom coated foil lidding.

[0043] EXAMPLE 1.

[0044] Stability Testing to Evaluate Resin 6013 with Candidate Formulations of

ACTABOND ^® Topical Skin Adhesive at 50°C.

[0045] The purpose of the stability study was to enable the selection of a final formulation and sterilization method to be used for ACTABOND ^® topical skin adhesive.

Samples used for this testing consisted of the liquid adhesive formulation packaged in the primary container, a cyclic olefin copolymer (COC) vial, to be used for commercial distribution. The COC resin of the vials in this study was grade 6013.

[0046] Samples in the study were stored at accelerated conditions of 50°C/ambient humidity in order to evaluate the performance of each candidate formulation with regard to viscosity. A subset of candidates was also evaluated for moisture content. All samples in this study were evaluated for viscosity. Four candidates and one control sample were also to be tested for moisture content.

[0047] Storage Conditions and Testing Frequency

[0048] Samples in this study were stored at accelerated conditions of 50°C/ambient humidity and tested according to the schedule described in Table 1 below. V = Viscosity, M = Moisture (Candidates 1-EB-10, l-EB-20, 1-CB-10, l-CB-20 and l-Control only)

[0049] Table 1. Testing Frequency and Requirements

[0050]

[0051] The total number of candidate formulation iterations in this study was 46, which included 4 non-irradiated controls. As the study progressed, a portion of the candidates demonstrated better performance than others due to differences in formulation components and radiation exposure levels during processing. Therefore, the underperforming candidates were discontinued prior to the 64-day test interval. Further, because viscosity was the primary stability indicating assay in this study, the moisture determinations were not executed.

[0052] Results

[0053] The data collected in this study is shown in Tables 3- 5 below. The results of testing indicate that candidate 6-EB-10 demonstrated the best stability as measured by the lowest change in viscosity from baseline. Candidate 6-EB-10 is comprised of the combination of optimized formulation components described in Table 2, as was irradiated at a dose of 10 kGy by electron beam radiation. This formulation remained within the terminal specification limit for viscosity (l20cP) after storage for 64 days at the accelerated storage condition of 50°C (l22°F), and thus has been selected as the optimum commercial formulation.

[0054] Table 2. Components of the Commercial ACTABOND ^® Adhesive Device

Formulation

[0055] Table 3.

[0056]

[0057] Table 4. [0058]

[0059] Table 5.

[0060]

[0061] Table 6. [0062]

[0063] Table 7.

[0064] To ensure that moisture and air borne impurities are not introduced into the vial during the filling operation, dry nitrogen is pumped into the vial just prior to filling. This process ensures that the head space remaining in the vial after filling and sealing is inert. The sealing parameters (temperature, pressure, and dwell time) have been optimized to provide a leak-free seal of the foil lidding to the vial as shown in Table 8.

[0065] Parameters for the sealing operation are designated for two separate machine stations. The pre-sealing station is first, where the foil lid is placed onto the vial after the foil lid is cut from roll stock, and the sealing station is second, where the foil lid is secured to the vial. The parameters for shown in Table 8 below. In a preferred embodiment, the pre seal parameters are 155 °C, 0.4 sec, and 60 psi, and the sealing parameters are 150 °C/ 2.5 sec/ 50 psi respectively.

[0066] Table 8

[0067] The filling machine includes a pre-sealing station and sealing station, and cycles within a period that allows for adequate cooling post-sealing to create an optimal seal. The machine incorporates a turntable that moves a set of for vials through each of seven (7) stations. The turntable rotates every 7.4 seconds, which allows all stations to complete their individual cycles. The station that removes the vials from the turntable immediately follows the sealing station, so the vials cool for a period of about 7.4 seconds before exiting the filling machine via a chute to a collection bin. The cooling time must be greater than about 2 seconds.

[0068] The final sealing process was verified through vacuum decay testing, which is sensitive to a one pascal pressure differential. Using this method, the sealing process has been verified as leak-free, which ensures a secure barrier against moisture penetration.

[0069] The sealing process has also been verified through dye penetration testing to provide an atmospheric barrier. Filling of the adhesive in the vial is performed in a Class 100,000 clean room to minimize any potential particulate contamination. Table 9 below includes data for the vacuum leak testing.

[0070] Table 9. VACUUM LEAK TESTING

Timers

Chamber Closing: 0.50 sec

Seal Inflating: 0.00 sec

Cycle 1

Equalizing: 1.00 sec

Testing: 1.00 sec

Cycle 2

Evacuation: 10.00 sec

Equalizing: 10.00 sec

Testing: 10.00 sec

Venting: 2.00 sec

Cycle 1

Min Test Vacuum: 150.0 MB

Max Test Vacuum: 900.0 MB

Min Differential Vacuum: -15 Pa

Max Differential Vacuum: 900 Pa

Cycle 2

Min Test Vacuum: 0.0 MB

Max Test Vacuum: 90.0 MB

Min Differential Vacuum: -15 Pa

Max Differential Vacuum: 900 Pa

Test # / Time MB Pa MB Pa

Cycle 1 Cycle 2

1 13 :33 :27 333.3 3 6.0 19

2 13 :34:24 333.3 5 5.9 18

3 13 :35:30 334.3 4 5.8 18

4 13 :36:33 335.0 4 5.7 17

5 13 :37:31 335.0 4 5.7 16

6 13 :38:25 334.5 4 5.6 15

7 13 :39: 18 335.0 4 5.6 15

8 13 :40:33 335.5 4 5.7 16

9 13 :41 :44 335.7 4 5.7 16

10 13 :42:47 335.5 6 7.4 60

11 13 :43 :54 335.5 6 7.1 55

12 13 :44:52 335.2 4 5.5 15

13 13 :45:51 335.2 3 5.6 15

14 13 :47:00 335.9 4 5.7 15

15 13 :47:57 335.7 4 5.7 15

16 13 :48:52 334.7 3 5.7 15 17 13:49:57 335.9 3 5.7 16

18 13:51 :05 335.7 4 5.7 16

19 13:52:05 335.5 4 5.7 17

20 13:52:55 335.5 4 5.7 15

21 13:53 :49 335.5 4 5.7 16

22 13:54:47 335.2 5 5.7 16

23 13:55:46 335.2 4 5.7 15

24 13:56:59 335.0 5 5.8 16

25 13:58:08 335.0 6 5.8 18

26 13:59:23 335.0 6 5.9 18

27 14:00:34 334.7 5 5.9 15

28 14:01 :32 334.7 4 5.9 17

29 14:02:34 335.5 4 5.9 16

30 14:03:45 335.5 5 5.9 17

31 14:04:54 335.5 4 5.9 17

32 14:05:58 335.2 4 5.9 18

33 14:07:20 335.5 4 5.9 18

34 14:08: 17 335.0 5 5.9 18

35 14:09:20 335.0 4 5.9 17

36 14: 10: 19 334.7 3 5.9 15

37 14: 11 : 15 334.7 5 5.9 17

38 14: 12:04 334.5 6 5.9 17

39 14: 12:54 334.7 4 5.9 18

40 14: 13 :54 334.7 4 5.9 18

41 14: 15:05 335.2 3 6.0 18

42 14: 16: 14 335.5 5 6.0 12

43 14: 17:21 335.0 6 6.0 17

44 14: 18: 18 335.0 5 6.0 18

45 14:19:28 335.0 5 6.1 18

46 14:20:39 335.0 5 6.1 16

47 14:21:37 334.7 4 6.1 18

48 14:22:31 334.7 4 6.1 19

49 14:23 :56 334.5 5 6.1 19

50 14:24:56 334.7 5 6.1 17

51 14:26:08 334.5 5 6.2 18

52 14:27:23 334.0 5 6.2 19

53 14:28:36 334.3 4 6.2 18

54 14:29:35 334.3 5 6.2 17

55 14:30:50 334.0 5 6.2 19

56 14:31 :56 334.0 5 6.2 18

57 14:32:58 333.8 5 6.1 17

58 14:33 :52 334.0 5 6.1 16

59 14:35:02 333.8 5 6.1 17

60 14:36:06 333.8 5 6.1 16

61 14:37:23 333.6 5 6.1 17

62 14:38: 15 334.5 4 6.1 17

63 14:39: 10 333.6 5 6.1 15

64 14:40:01 333.3 5 6.1 16

65 14:40:57 334.5 5 6.0 16

66 14:42:28 334.5 5 6.1 16

67 14:43 :42 334.3 5 6.1 16

68 14:44:37 334.0 5 6.1 16

69 14:45:36 334.0 6 6.1 15

Summary Total: 69

Failed: 0 0.00%

[0071] Sterilization Process

[0072] After the vial is filled with adhesive and the vial and sealed, the system (vial, seal, adhesive formulation) is sterilized to a sterilization acceptance level (SAL) of 10 ⁶ using electron beam radiation. The dose of electron beam radiation has been selected to ensure optimal stability of the adhesive formulation. The electron beam sterilization dose for design verification was a minimum of 10 kilogray (kGy). The commercial process has been validated for a minimum dose of 8 kGy. The acceptable range for sterilization of the vials is from about 8 to about 10 kGy.

[0073] The vials are oriented in a single layer during exposure to electron beam radiation in order to minimize the variation in radiation dose between vials and allow for the lowest possible dose that yields performance within specifications. The COC material of the vial (6013 resin) has been selected to be compatible with electron beam radiation. The nitrogen head space of the adhesive in the vial reduces the potential for oxidation associated with an ambient air headspace when exposed to the irradiation process. The speed of the conveyer is determined in order to assure that the acceptable dosage range is achieved.

[0074] Plug Coating Process

[0075] Porous plugs, which are preferably formed from polyethylene, such as Porex

PSU -691, are incorporated in an applicator and coated with a polymerization initiator (e.g. benzalkonium chloride (BZC)) to ensure consistent setting / polymerization performance. The process for coating the plugs includes solubilizing the benzalkonium chloride in a solvent (e.g. acetone), saturating the plugs in the solvent solution, then evaporating the solvent in order to leave a specific amount of benzalkonium chloride residue uniformly on the plugs. The target weight is between about 5 and about 10 mg of BZC per plug. In a preferred embodiment the weight of BZC is 7 mg per plug. [0076] The plug coating process involves tumbling the plugs in specially designed glassware with internal ridges to agitate the plugs to ensure even distribution of benzalkonium chloride from plug-to-plug. The plugs are further subjected to partial vacuum and agitation during drying to ensure even distribution of benzalkonium chloride plug-to-plug.

[0077] Assembly Process

[0078] Assembly of the applicator is performed in a Class 100,000 clean room to minimize particulate contamination. One such applicator is depicted in U.S. Pat. No. 8,852,231. Other applicators are contemplated to be within the scope of the present invention. The applicator is packaged in a foil pouch to prevent moisture penetration. The foil used to package the applicator is specified to be sufficient thickness and defect free to maximize its function as a moisture barrier. The foil pouch used to package the applicator incorporates a TYVEK ^® header that allows for the package to be terminally sterilized by ethylene oxide (EO) prior to final sealing. The header allows the EO to penetrate the applicator to assure full saturation with EO gas for sterility, and also allows for complete EO dissipation within an optimal amount of time.

[0079] Terminal Sterilization Process

[0080] The assembled device as packaged in its final packaging configuration is sterilized to a SAL of 10 ⁶ by exposure to ethylene oxide gas. The ethylene oxide sterilization cycle has been developed to incorporate shallow vacuum cycles (0.5 atmosphere) to maintain the integrity of the seal on the vial (primary package). The ethylene oxide sterilization cycle has been developed to incorporate slow evacuation and charge rates to maintain the integrity of the seal on the vial (primary package). Process parameters are shown in Table 10 below.

[0081] Table 10. Process Parameters for Terminal Sterilization

SET POINT MINIMUM MAXIMUM

Preconditioning Temperature: 115 °F 105 °F 125 °F

Relative Humidity: 60% 40% 80%

Time: 24 Hours 24 Hours 72 Hours

110 °F 100 °F 115 °F

Processing Temperature

Initial Vacuum Evacuate To: 18.5 inHgA 19.0 inHgA 18.0 inHgA

Time: 10 Minutes 5 Minutes N/A

Differential Tolerance: ± 0.5 inHg Leak Test

Hold Time: 5 Minutes 5 Minutes 60 Minutes

Inject To: 29.0 inHgA 28.5 inHgA 29.5 inHgA

Inert Dilution

5 Dilutions Total

18.5 inHgA 19.0 inHgA 18.0 inHgA

Evacuate To:

Humidification Inject To: 19.5 inHgA 19.0 inHgA 20.0 inHgA Humidity Dwell Maintain Pressure: 19.5 inHgA 19.0 inHgA 20.0 inHgA Time: 80 Minutes 70 Minutes 90 Minutes

EtO Inject Inject To: 29.0 inHgA 28.5 inHgA 29.5 inHgA

Time: 20 Minutes 10 Minutes N/A

Temperature: 110 °F 105 °F 115 °F

EtO Dwell

EO Makeup

Maintain Pressure: 29.0 inHgA 28.5 inHgA 29.5 inHgA Time: 361 Minutes 360 Minutes 390 Minutes

Evacuate To: 15.0 inHgA 14.5 inHgA 15.5 inHgA

After Vacuum

Time: 10 Minutes 5 Minutes N/A

Inject To: 29.0 inHgA 28.5 inHgA 29.5 inHgA

Gas Wash“A”

Inert Inject

4 Washes Total

Time: 10 Minutes 5 Minutes N/A

Evacuate To: 18.5 inHgA 19.0 inHgA 18.0 inHgA Time: 10 Minutes 5 Minutes N/A

Inject To: 29.0 inHgA 28.5 inHgA 29.5 inHgA

Gas Wash“B”

Air Inject

3 Washes Total

Time: 10 Minutes 5 Minutes N/A

Evacuate To: 18.5 inHgA 19.0 inHgA 18.0 inHgA Time: 10 Minutes 5 Minutes N/A

Release To: 28.5 inHgA Atmospheric Atmospheric

Final Release

Time: 10 Minutes 5 Minutes N/A

Temperature: 110 °F 100 °F 120 °F

Aeration

Time 24 Hours 24 Hours 96 Hours

[0082] Although the invention has been described and illustrated with respect to exemplary embodiments thereof, it should be understood by those skilled in the art that the foregoing and various other changes, omissions and additions may be made therein and thereto, without parting from the spirit and scope of the present invention. Accordingly, other embodiments are within the scope of the following various embodiments